Alzheimer disease is the fourth leading cause of death in adults. The development of effective therapeutic and diagnostic tools to combat this disorder has been hampered by an incomplete knowledge of the biochemical pathogenesis of this disorder. One potential avenue which could be exploited to resolve this is to isolate the gene(s) causing the autosomal dominant form(s) of Familial Alzheimer Disease (FAD). One FAD gene has been mapped to chromosome 21. In the absence of a clear biochemical candidate, the FAD gene on chromosome 21 can be isolated providing that it can be precisely localized to a small region of chr 21. Although this purely genetic strategy has been successful in Cystic Fibrosis and Duchenne Muscular Dystrophy, its application to FAD will require specialized strategies to improve the informativeness of available FAD pedigrees (which is reduced by the late age of onset of symptoms and short subsequent lifespan of affected individuals), and to maximize the likelihood that an etiologically homogeneous group of pedigrees are being examined. We therefore propose to apply a series of highly informative polymorphic markers (> 3 alleles) from the proximal chromosome 21 which can be assayed by Polymerase Chain Reaction (PCR) and which therefore will allow the inclusion of additional data from deceased affected individuals for whom only formalin fixed tissue is available. We will concentrate our efforts upon four groups of pedigrees with clear autosomal dominant transmission and with probable founder effects, thereby minimizing the risk of inclusion of non-allelic forms. More importantly, we will employ two additional strategies which will complement the purely genetic paradigm. First, we will define and clone the breakpoints of translocations involving proximal chromosome 21 in at least four pedigrees where individuals carrying these translocations develop presenile AD. A similar strategy has recently permitted the cloning of the Neurofibromatosis 1 gene. We will investigate genomic DNA from the vicinity of these AD related translocations for expressed sequences which might represent the FAD gene. Second, we will employ two different subtractive cloning strategies in order to directly isolate candidate expressed sequences encoded on the proximal long arm or short arm of chromosome 21. We will examine the candidate genes derived by both strategies for genetic linkage to FAD in our pedigrees, and we will compare their tissue specific expression to that of the known neuropathology of AD.